One of the hallmarks of homeostasis is the regulation of cell proliferation. Current regulatory models of cell proliferation include mechanisms for activation, modulation and inhibition of cell growth processes. The goal to understand the mechanisms for regulating cell proliferation lead to the discovery of an enormous number of stimulatory growth regulators, also known as growth factors. The search for inhibitory growth regulators has not been as extensive.
Novel regulatory molecules may participate in the bidirectional regulation between the neuroendocrine and immune systems. Hence, products from the pituitary gland may alter immune cell function(s) since experiments have shown that pituitary hormones affect lymphoid cell function [Johnson et al. (1982) Proc. Natl. Acad. Sci. U.S.A. 79: 4171-1414; Blalock et al. (1984) Biochem. Biophys. Res. Commun. 125: 30-34; and Lolait et al. (1984) J. Clin. Invest. 73: 277-280], and that lymphoid cells can synthesize and secrete pituitary hormones when stimulated by the appropriate hypothalamic releasing hormones [Smith et al. (1986) Nature (London) 322: 881-882].
Suppressin (SPN) is a novel regulatory molecule of neuroendocrine origin that inhibits cell proliferation. The size of SPN (M.sub.r 63,000) and its monomeric molecular structure are two characteristics relative to other endogenous inhibitors of cell proliferation, which indicate that it is novel. Transforming growth factor-beta (TGF-.beta.) [Roberts et al. (1983) Biochemistry 22: 5692-5698; Roberts et al. (1985) Cancer Surveys 4: 683-705; and Massague (1984) J. Biol. Chem. 259: 9756-9761] and hepatic proliferation inhibitor (HPI) [McMahon, et al. (1982) Proc. Natl. Acad. Sci. U.S.A. 79, 456-460; Huggert, et al. (1987) J. Cell. Biochem. 35, 305-314; and McMahon (1984) J. Biol. Chem. 259, 1803-1806] are two endogenous inhibitors of cell proliferation for which the most information is available regarding their structure and biological activities. In contrast to SPN, both proteins are smaller than SPN (TGF-.beta., M.sub.r 25,000: HPI, M.sub.r ranging from 17-19,000 to 26,000) and they are secreted as homodimers. Additionally, SPN and HPI differ in their isoelectric point with SPN having a basic pI (8.1) and HPI with a pI of 4.65. SPN, TGF-.beta. and HPI are similar in a general sense because they inhibit cell proliferation without showing cytotoxic effects. For example, TGF-.beta. and HPI have been shown to inhibit epithelial cell proliferation in the presence of mitogens (Huggert et al.). Similarly, SPN inhibits splenocyte proliferation in the presence of mitogens. The specific differences in target tissues for the inhibitory activities of these three proteins suggests that they have distinct physiological functions. These three inhibitory molecules differ in the cell types affected as well as in their 50% inhibitory dose (ID.sub.50). TGF-.beta. has been shown to inhibit cells from several tissue types indicating that it is relatively nonselective [Roberts, et al. (19) Proc. Natl. Acad. Sci. U.S.A. 82: 119-123; and Tucker et al. (1984) Science 226: 705-707]. HPI and SPN are apparently more restricted in that they inhibit cells of hepatic origin (Huggett, et al. and Iype (1984) Mol. Cell. Biochem. 59: 57-80) or lymphoid origin, respectively. TGF-.beta., HPI and SPN inhibit cell proliferation at low molar concentrations. The ID.sub.50 of SPN for splenocytes (2.8.times.10.sup.-9 M) is higher than the ID.sub.50 of TGF-.beta. (10.4.times.10.sup.-12 M) and HPI (2.5.times.10.sup.-12 M) for rat liver epithelial cells (Huggett et al.) suggesting that they may be more potent inhibitors of cell proliferation than SPN. However, a wide variation has been observed in the response of cells to the same concentration of SPN indicating that response depends on the target cell. The structural and biological data obtained on SPN thus indicate that it is novel and different from TGF-.beta. and HPI.
The significance of SPN is important since its biological activity is cytostatic and not cytotoxic. SPN may function as an endocrine, paracrine or autocrine modulator of cell proliferation. The production of neuroendocrine hormones that affect cells of the immune system suggests these hormones have a role as immunoregulatory molecules. If circulating neuroendocrine hormones, including SPN, directly affect immunocytes in vivo, then these hormones have paracrine or autocrine functions within the immune system. The de novo synthesis of SPN by GH.sub.3 cells, its presence in normal tissues and the response of target cells (splenocytes) suggests endocrine regulation of the immune system.
Accordingly, SPN functions as an autocrine regulator of cell proliferation, especially since it has recently been detected in lymphocytes. The demonstration that primate kidney cells produce TGF-.beta. [Tucker, et al. (1984) Proc. Natl. Acad. Sci. U.S.A. 81: 6757-6761], possesses receptors for TGF-.beta. [Sporn, et al. (1985) Nature (London) 313: 745-747], and that their growth is inhibited by TGF-.beta. (Tucker et al., 1984; Sporn et al., 1985) supports the general hypothesis that cell proliferation is controlled by autocrine regulation. Similar experiments with SPN and lymphocytes suggests that SPN is an autocrine regulator of lymphocyte proliferation, much in the same manner that TGF-.beta. regulates kidney growth.